It is well established that in a variety of normal and pathophysiological conditions, the manifestation of muscle fatigue is attributable to mechanisms that extend from the forebrain of the central nervous system (CNS) to the contractile machinery of single fibers in active muscles. Knowledge about the neural and neuromuscular aspects of fatigue is, however, far less complete than that about purely muscular mechanisms. This imbalance is attributable largely to the need to gain more information on the mechanisms underlying the repetitive firing of INs throughout the entire CNS, and of MNs within the brain and spinal cord. In this proposal, the focus is first on the repetitive firing properties of spinal motoneurons (MNs) and, to lesser extent, ventral-horn interneurons (INs). It is shown that by gaining more information on two key firing-rate properties, the stimulus current (I) -spike-frequency (f) relationship of MNs and the spike frequency adaptation (i.e., the f drop over time) of MNs and INs, it should be possible to provide insight into fundamental spinal mechanisms associated with muscle fatigue. Next, it is shown how information on MN firing patterns has significance for the force developed by motor units in fresh and fatigued muscle. This involves consideration of the associations between the I-f relationship, the spike-frequency adaptation of MNs, the activation frequency (f) -force (F) relationship of the motor units supplied by the MNs, and the F development by motor units over time. The overall approach, has two specific aims. First, to explore the spinal neuromodulation of the intrinsic I-f relationship of MNs and the spike-frequency adaptation of spinal MNs and INs, and, next, to use the MN component of the results to explore the I-F relationship and F drop over time of motor units in fresh and fatigued muscle. The intent is that these studies will contribute fundamental information on the cellular neurobiology of muscle fatigue and as such, contribute to the scientific basis that must underlie future clinical approaches to the study of muscle fatigue. Clinical fields like motor-control orthopedics, motor-control rehabilitation, functional electrical stimulation and motor prosthetics require a foundation that includes a substantial component of fundamental neuroscience including, in particular, a far deeper understanding of how the repetitive firing properties of spinal INs and MNs are translated into movement in fresh, fatigued and pathophysiological states.